Abstract
1,3-Dioxolane-based compounds (2-14) were synthesized, and the pharmacological profiles at alpha(1)-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)). Compound 9, with a pA(2) of 7.53, 7.36, and 8.65 at alpha(1A), alpha(1B), and alpha(1D), respectively, is the most potent antagonist of the series, while compound 10 with a pA(2) of 8.37 at alpha(1D) subtype and selectivity ratios of 162 (alpha(1D)/alpha(1A)) and 324 (alpha(1D)/alpha(1B)) is the most selective. Binding assays in CHO cell membranes expressing human cloned alpha(1)-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of alpha(1)-adrenoceptor antagonists.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-1 Receptor Antagonists*
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Adrenergic alpha-Antagonists / chemical synthesis*
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Adrenergic alpha-Antagonists / chemistry
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Adrenergic alpha-Antagonists / pharmacology
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Adrenergic beta-1 Receptor Antagonists
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Animals
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiology
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CHO Cells
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Cricetinae
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Dioxolanes / chemical synthesis*
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Dioxolanes / chemistry
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Dioxolanes / pharmacology
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Humans
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In Vitro Techniques
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Ligands
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Male
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Radioligand Assay
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Rats
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Rats, Wistar
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Spleen / drug effects
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Spleen / physiology
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Structure-Activity Relationship
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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4-(2-(2-methoxyphenoxy)ethylaminomethyl)-2,2-diphenyl(1,3)dioxolane
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4-(2-phenoxyethylaminomethyl)-2,2-diphenyl(1,3)dioxolane
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Adrenergic alpha-1 Receptor Antagonists
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Adrenergic alpha-Antagonists
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Adrenergic beta-1 Receptor Antagonists
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Dioxolanes
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Ligands